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Malaria is one of the
world's most inexorable killers, claiming about
1.3 million people a year. Now a new drug,
partly developed in Melbourne, may revolutionise
the fight against the disease.
IT
WOULD not be the first time that the Boeing 747
has been used to illustrate a point. But the
analogy used by Melbourne scientist Professor
Bill Charman is confronting — the number of
children under five years of age who die from
malaria daily could fill more than seven jumbo
jets. That's the equivalent of a child dying
every 30 seconds.
"Just terrible," says Charman,
shaking his head.
Malaria kills about 1.3
million people a year. Many millions more become
infected, mostly Africans and populations across
Asia and South America. Right now, as many as 5
million people in Tanzania and Mozambique have
the disease, caused by the bite of an infected
female anopheles mosquito. Nearly 2 million
people have it in India, 400,000 in Brazil,
200,000 in Indonesia.
Malaria, by numbers, is a
nightmare. But in the hunt for a cheap and easy
cure for one of the world's most relentless
killers, the numbers 277 and 439 have assumed
monumental significance and look to be cardinal
signposts to a new way of battling global
diseases.
Both numbers refer to
variations of a stunning anti-malarial drug
part-developed in the laboratories of Monash
University, an ozonide dubbed "OZ" whose design
started from the proven malaria fighter
artemisinin, which is extracted from the
wormwood plant Artemisia annua, used for
centuries by the Chinese as a herbal remedy.
But the OZ compounds have
been forced onto diverging paths by a
combination of economics and necessity.
OZ277, launched with
international fanfare in August 2004 with the
promise of a simple three-day oral treatment for
sufferers, continues through laborious human
trials conducted by the big Indian
pharmaceutical company Ranbaxy.
Now OZ439, developed as a
next generation drug candidate and not yet
paraded publicly, could well supersede its
talented older sibling and provide medicine's
silver bullet — a combined one-shot treatment
and preventative drug, costing less than $1, a
breakthrough that stands to revolutionise the
fight against malaria.
Though the scientists who
created OZ are deliberately cautious about 439's
prospects, their new incarnation offers a
compelling case for optimism. "Our confidence is
high," says Charman, the head of the Monash
Institute of Pharmaceutical Sciences and a
driver of the project. "How you quantify (that
optimism), I don't know."
Adds Professor Susan Charman,
a partner scientist who specialises in drug
design and development chemistry: "We're four
years further on. We've got four years more
knowledge. Right now, based on all the available
data, OZ439 looks better than OZ277 … but
there's a long way to go."
The wonderful story of OZ
typifies the highs and lows of major drug
discovery and development, and also the glacial
speed at which such enterprise progresses.
It is a narrative in which
science, philanthropy and big business
intersect, one whose principal cast includes a
unique partnership of scientists from Melbourne,
Nebraska in the US and Basle in Switzerland, as
well as a Geneva-based non-profit organisation
that is a go-between for science and Big Pharma,
and global donors headed by Microsoft founder
Bill Gates, whose altruism comes in
multimillion-dollar licks and who has sounded a
clarion call for malaria's eradication.
OZ is also a story that
challenges the convention of pharmaceutical
behemoths spending billions of dollars on drug
research in the hope of a once-in-a-lifetime
lollapalooza: think Pfizer and the
cholesterol-buster Lipitor, Ely Lilly and the
anti-depressant Prozac. That model might be
tolerated by developed economies seeking drugs
to treat Western disorders. But it's unlikely to
support the search for a cure for the ills of
the world's poor, in communities that survive on
a pittance and where drugs need to be supplied
dirt-cheap.
Enter the Medicines for
Malaria Venture, a non-profit "start-up" that
carries the blessing of the World Health
Organisation as well as some of the globe's
biggest drug makers. Established at the start of
the decade, MMV uses innovative public-private
partnerships that connect academia with industry
on a single-minded mission to beat malaria. It
has 30 projects on its books.
"Last year just 17 or so new
drugs were approved in the world," says Bill
Charman. "Given the billions of dollars the
pharmaceutical industry spends on research,
that's a pretty ordinary return. I'd suggest the
model isn't working." But MMV, spending just $50
million a year on its collaborative works, is
providing a counterpoint.
Part of MMV's raison d'etre
was growing concern that the world's
anti-malarial weaponry was being steadily
depleted by the malaria parasite's powerful
ability to mutate and build resistance. Cheap,
accessible medicines such as chloroquine, the
synthetic quinine that for years led the fight,
have all but lost their sting and health
authorities have become increasingly protective
of artemisinin lest it go the same way.
A dictum issued a few years
ago by the world's leading public health body
raised the stakes: WHO insisted that artemisinin-based
treatments must be combination therapies — that
is, delivered with a compatible second drug
similar to treatments for AIDS and tuberculosis
— thereby making it tougher for the parasite to
fight back.
But the OZ project was
largely driven by price and availability.
Therapies using artemisinin derivatives were
costing up to 10 times as much as standard
medicines and were in short supply due to the
vagaries of artemisia production. (The plant,
which takes about 18 months to grow, is farmed
mostly in China and Vietnam.) With demand for
artemisinin-based treatments rising towards 200
million a year, what the world needed was a
synthetic version that could be mass-produced.
"What we wanted was something
that was completely synthetic," says Anna Wang
of MMV. "Something that mimicked what
artemisinin does. Otherwise you are left
dependent on the weather, on farmers … and the
cost is unstable."
MMV contrived a suitable
partnership to crack artemisinin's code, its
"arranged marriage" putting Bill and Susan
Charman of Monash University together with
renowned researcher Jonathan Vennerstrom of the
University of Nebraska Medical Centre. The team
included scientists from the Swiss Tropical
Institute in Basle, with input from experts at
neighbouring Hoffman-La Roche and from Fulcrum
Pharma in the UK.
A complex partnership strung
out across the globe might not have been
manageable even 10 years ago. "Without email and
FedEx I think it would be next to impossible,"
laughs Vennerstrom now.
The partnership was as
careful a construction as a molecule itself,
drawing on complementary expertise: Vennerstrom
built the synthetic molecules that would be the
foundation of OZ, the Swiss tested them in
cultures in which the parasite was growing,
while Monash University's Parkville laboratories
worked on the drug's chemical and metabolic
properties, fine-tuning the compound to make it
more effective.
The scientists were never
going to replicate the whole molecule that is
artemisinin "because there were 12 or 13 steps
and it was just not practical," Susan Charman
says. "It would be far too expensive and too
difficult."
What the team did learn was
how to replicate in just a few steps the key
part of artemisinin that delivers its
anti-malarial clout, something that chemists
call an endoperoxide bridge where two oxygen
molecules link together. In the body, the oxygen
atoms in the OZ drugs are programmed to react
with iron that is released when the parasite
feeds on infected blood cells, destroying the
parasite in the process.
But this type of molecule is
typically unstable, something the researchers
had to overcome with their copy compound. Their
end product, delivered after 277 painstaking
attempts, was a synthetic peroxide that was
stable and an ultra-efficient killer of the
Plasmodium falciparum parasite, responsible
for the most lethal strain of malaria.
The result drew worldwide
acclaim. OZ277 immediately entered trials
conducted by Ranbaxy, passing safety and
toxicology tests with flying colours, before
being tested on healthy human volunteers. "And
it was terrific," Bill Charman says. "There were
no adverse effects at doses much higher than we
expected to be needed. It was a very safe, clean
molecule.
"And phase one is where a lot
of compounds will fail, because you can test
them on mice and rats and dogs but, ultimately,
there's only one species that you've got to get
right. But we went through phase one and there
weren't any serious issues at all."
OZ277 was headed for phase
two, where it would be tested on malaria
sufferers.
Meanwhile, the OZ team kept
working on their potential world-beater "because
drug discovery never stops", Susan Charman says.
"You can always improve certain properties. It's
just a continual process."
This is also where MMV's
public-private model of drug development
digresses from the general practice of Big
Pharma. Producing a next-generation follow-up
compound is not always the inclination of Big
Pharma, whose research efforts are often
diverted once a first compound becomes its
candidate for clinical trials.
Being first out of the blocks
can be critical in securing windfall returns.
But being first can also mean rivals can track a
new drug's progress through patents, allowing
them to work quietly on copy compounds while the
original drug is being trialled.
Pfizer's erectile dysfunction
wonder-drug Viagra is an example. It was the
first of its type, delivered in the late 1990s,
but a next-generation version, Eli Lilly's
Cialis, was on the market within four years.
"The problem is Pfizer had
already invested in the Viagra brand," Bill
Charman explains. "It doesn't want to have to
come along later and say, 'Actually, we've got a
better one'. So you don't tend to get 'Viagra
2', for instance. The company moves on looking
for the next big thing."
But MMV doesn't work like
that, because the profit motive is largely
absent and its enterprise is partly supported by
universities such as Monash and Nebraska that
are looking for impact and a different kind of
kudos from their research. Getting a prototype
into the clinic allows its creators to watch for
deficiencies and then correct them by creating
superior compounds. In the case of the OZ
program, 277 did, ultimately, have a few
problems.
"We came to a crossroads,"
MMV's Anna Wang says. "We were fast-tracking 277
because we desperately wanted the synthetic
version and because we didn't know when we would
encounter resistance to the artemisinin class of
drugs. I think at that point, around 2004, we
were thinking that maybe by 2010 we could have
this next-generation drug.
"But drug development is a
risky business. When we got to phase two, where
you actually test the drug on patients with
malaria, we hit some hurdles. Basically, we
thought we needed a certain amount of the drug
to beat the malaria. In fact, it looked like we
might need more, which would obviously have
implications for the cost of the drug."
Because of the ongoing nature
of their investigations, the OZ researchers were
already looking at ways of ensuring that their
new drug stayed in the bloodstream longer so
that it could kill more of the parasites, more
quickly.
But about the same time, the
multinational team assembled in India for
meetings with Ranbaxy. Almost by accident they
had an epiphany.
One of the difficulties of
treating malaria sufferers in Third World
conditions is getting patients to complete a
course of treatment. A seven-day program is
fraught: nomadic people can lose track of their
drugs, and sometimes adults who start feeling
better after a few doses save the rest of the
course in case their child gets sick.
OZ277 was promising to
deliver that regimen in just three doses, a big
improvement on the prevailing standard for most
anti-malarial medicines. But the research team
asked themselves why they hadn't gone all-out
for a one-day cure.
"It was pretty obvious," Bill
Charman says. "The issue for refugees is that
some are arriving in camps already with malaria.
But if you had a single oral dose … there's no
compliance issue."
The two events conspired, and
more than 100 compounds later, Susan Charman's
team of 20 or so scientists in Melbourne had
found a way of prolonging the life of the OZ
compound, paving the way for a one-dose
treatment. Further, the team was able to
reconstruct the OZ molecule so that it also
carried prophylactic qualities that were as
effective as some of the widely marketed brands,
but faster acting — something that the original
artemisinin-based treatments did not have.
"We got our so-called
Viagra-2," says Bill Charman with a laugh. And
how!
The breakthrough upped the
ante, creating an immediate dilemma for MMV,
which was funding much of the OZ research and
had awarded OZ277 its "project of the year" in
2001. Reluctantly, it withdrew support for 277
and Ranbaxy's trials, focusing its energy — and
donor funds — on the new generation of ozonides
that the research team was now producing, and by
the end of 2006 the OZ team had won "project of
the year" for a second time.
In the end, the team looked
to be spoiled for choice. Several of the
next-generation compounds looked terrific, but
in March they finally chose number 439 as their
new candidate for trials.
"I think for Susan and Bill,
picking 439 was really difficult," MMV's Wang
says. "There were at least two other compounds
that looked similar but were a little bit
different. But for them to say 'OK, we'll take
this one', that's a bit like picking a horse in
a race. You'd like to be able to pick two or
three to be sure, but we're just not in a
position to be able to (fund) that."
RIGHT
now, 439 is being put through its — very
preliminary — paces, being tested for safety in
animals. But the team has already conducted
early toxicology tests "and those have looked
very good", Susan Charman says. But the switch
to 439 means the researchers have lost time:
they do not expect the new drug to be tested in
malaria sufferers before 2010. All going well,
it could hit the market by 2014.
Meanwhile, Ranbaxy is pushing
ahead with OZ277, now coded RBx-11160. In a
statement issued to The Age, it confirmed
that phase-two trials were progressing in
Thailand and India, and that regulatory approval
had been sought for trials involving children in
Kenya and Tanzania.
The scientists say it is
possible that the two OZ therapies will both
succeed. OZ277 could be destined for India's
middle class if it does end up costing more than
originally hoped, while a dirt-cheap 439 could
be the hope of sub-Saharan Africa.
"Drug discovery is not an
exact science," says Omaha-based researcher
Jonathan Vennerstrom. "It's a bit like weather
forecasting. Sometimes you're way off, sometimes
you're somewhat accurate … but if you're getting
good communication and good data sharing then
that helps a lot."
Nor is it inconceivable that
an even better OZ compound could emerge down the
track. "One never knows," adds Vennerstrom. "And
that depends upon the people who fund this MMV
project. What their opinion would be if
something goes wrong with 439. Do we view it as
a serious liability to the whole class of
compounds?"
Though the future can never
be certain, that outcome seems unlikely. Says
Anna Wang: "The whole class of compound is very,
very potent. That we're sure of … I would say we
are quite sure that something will come out of
this class."
Simon Mann is a senior
writer.
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